Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (A beta Os) has been implicated in AD pathogenesis: however, the molecular events underlying a role for A beta are not well understood. We studied the effects of A beta Os on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that A beta Os treatment caused a reduction in total Mfn1 after a 2 h exposure (42 +/- 11%); while DRP1 increased at 1 and 2 h (205 +/- 22% and 198 +/- 27%, respectively), correlating to changes in mitochondrial morphology. We also observed that SIRT1 levels were reduced after acute and chronic A beta Os treatment (68 +/- 7% and 77 +/- 6%, respectively); while PGC-1 alpha levels were reduced with the same time treatments (68 +/- 8% and 67 +/- 7%, respectively). Interestingly, we found that chronic treatment with A beta Os increased the levels of pSIRT1 (24 h: 157 +/- 18%), and we observed changes in the PGC-1 alpha and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1 alpha interaction pattern after chronic exposure to A beta Os. Our data suggest that A beta Os induce important changes in the level and localization of mitochondrial proteins related with the loss of mitochondrial function that are mediated by a fast and sustained SIRT1/PGC-1 alpha complex disruption promoting a "non-return point" to an irreversible synaptic failure and neuronal network disconnection.